An antigen specific T cell response is mediated by two signals: first, engagement of the TCR with antigenic peptide presented in the context of MHC (signal 1), and second, a second antigen-independent signal delivered by contact between different receptor/ligand pairs (signal 2). This “second signal” is critical in determining the type of T cell response (activation versus tolerance) as well as the strength and duration of that response, and is regulated by both positive and negative signals from costimulatory molecules, such as the B7 family of proteins. The most extensively characterized T cell costimulatory pathway is B7-CD28, in which B7-1 (CD80) and B7-2 (CD86) each can engage the stimulatory CD28 receptor and the inhibitory CTLA-4 (CD152) receptor. In conjunction with signaling through the T cell receptor, CD28 ligation increases antigen-specific proliferation of T cells, enhances production of cytokines, stimulates differentiation and effector function, and promotes survival of T cells (Lenshow, et al., Annu. Rev. Immunol., 14:233-258 (1996); Chambers and Allison, Curr. Opin. Immunol., 9:396-404 (1997); and Rathmell and Thompson, Annu. Rev. Immunol., 17:781-828 (1999)). In contrast, signaling through CTLA-4 is thought to deliver a negative signal that inhibits T cell proliferation, IL-2 production, and cell cycle progression (Krummel and Allison, J. Exp. Med., 183:2533-2540 (1996); and Walunas, et al., J. Exp. Med., 183:2541-2550 (1996)). Other members of the B7 family include B7-H1 (Dong, et al., Nature Med., 5:1365-1369 (1999); and Freeman, et al., J. Exp. Med., 192:1-9 (2000)), B7-DC (Tseng, et al., J. Exp. Med., 193:839-846 (2001); and Latchman, et al., Nature Immunol., 2:261-268 (2001)), B7-H2 (Wang, et al., Blood, 96:2808-2813 (2000); Swallow, et al., Immunity, 11:423-432 (1999); and Yoshinaga, et al., Nature, 402:827-832 (1999)), B7-H3 (Chapoval, et al., Nature Immunol., 2:269-274 (2001)) and B7-H4 (Choi, et al., J. Immunol., 171:4650-4654 (2003); Sica, et al., Immunity, 18:849-861 (2003); Prasad, et al., Immunity, 18:863-873 (2003); and Zang, et al., Proc. Natl. Acad. Sci. U.S.A., 100:10388-10392 (2003)). B7-H1 and B7-DC are ligands for PD-1, B7-H2 is a ligand for ICOS, and B7-H3 remains at this time an orphan ligand (Dong, et al., Immunol. Res., 28:39-48 (2003)).
B7-H4 is member of the B7 family that is a negative regulator of T cell responses. Human and mouse B7-H4 share 87% amino acid identity, suggesting an important evolutionarily conserved function. Human and mouse B7-H4 mRNAs are expressed broadly in both lymphoid (spleen and thymus) and nonlymphoid organs (including lung, liver, testis, ovary, placenta, skeletal muscle, pancreas, and small intestine). Limited studies of B7-H4 protein expression indicate that B7-H4 is not expressed on freshly isolated human T cells, B cells, DC, and monocytes, but it can be induced on these cell types after in vitro stimulation. Immunohistochemical staining shows that B7-H4 is highly expressed in breast, renal, lung and ovarian tumors, and reverse transcriptase polymerase chain reaction (RT-PCR) analyses indicate that mouse B7-H4 also is highly expressed in a number of tumor cell lines, including prostate, lung, and colon carcinomas. B7-H4 is highly expressed by tumor associated macrophages (TAMs) and is present in tumor vasculature. Regulatory T cells (Tregs) induce upregulation of B7-H4 on TAMs via IL-6 and IL-10; this is thought to be one of the mechanisms by which Tregs contribute to immune suppression. (Kryczek, J. I., J. Immunol., 177(1):40-44 (2006)). B7-H4 expression has also been observed in tubule epithelial cells of diseased kidneys (Chen, Y., Kidney Int., 70(12):2092-9 (2006) Epub 2006 Oct. 18).
The receptor for B7-H4 has not been cloned. B7-H4 has been shown not to bind to known CD28 family members such as CD28, CTLA-4, ICOS, and PD-1 (Sica, et al., Immunity, 18:849-861 (2003)), and these are therefore not potential receptors for B7-H4. Functional studies using B7-H4 transfectants and B7-H4-Ig fusion proteins demonstrate that B7-H4 delivers a signal that inhibits TCR-mediated CD4+ and CD8+ T cell proliferation, cell-cycle progression and IL-2 production. B7-1 costimulation cannot overcome B7-H4-Ig-induced inhibition. In agreement with the in vitro activity, B7-H4 knock-out mice develop autoimmunity. The broad and inducible expression of B7-H4, together with functional studies, suggests that B7-H4 serves to downregulate immune responses in peripheral tissues.
More recent results demonstrate that B7-H4 also acts as a negative regulator of neutrophil response. Neutrophils are a key component of the innate immune system and are a first line of host defense against pathogens. However, neutrophils can also contribute to chronic inflammation and autoimmune disease. B7-H4 knockout mice display increased Th1 responses and are more resistant to infection by Listeria monocytogenes due to an augmented immune response that is neutrophil dependent (Suh. W. K., et al., Mol Cell Biol., 26(17):6403-11 (2006) and Zhu, G., et al., Blood, 113(8):1759-67 (2009) Epub 2008 Dec. 24). Mice hydrodynamically transfected with monomeric B7-H4 IgV domain or extracellular domain (ECD) increased neutrophil response to lipopolysaccharide (LPS) and Listeria infection, while dimeric B7-H4-Ig reduces proliferation of bone marrow derived neutrophil precursors (Zhu, G., et al., Blood, 113(8):1759-67 (2009) Epub 2008 Dec. 24).
Certain immune cells and immune cell signal transduction pathways are promising targets for new agents for treating immune disorders. For example Th1, Th17, Th22, and regulatory T cells (Tregs) play important roles in mediating autoimmunity and inflammation. Mounting evidence from numerous studies shows the importance of these immune cells in disorders such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, psoriasis, lupus erythematosus and uveitis. Most existing therapies target only one pathway at a time. Thus, there is a need for therapies that target multiple cells and pathways involved in autoimmunity and inflammation, such as Th1, Th17, Th22, Tregs, or other cells that secrete, or cause other cells to secrete, inflammatory molecules such as cytokines, metalloproteases, chemokines and other molecules, including, but not limited to, IL-1β, TNF-α, TGF-beta, IFN-γ, IL-17, IL-6, IL-23, IL-22, IL-21, IL-10 and MMPs.
Therefore it is an object of the invention to provide compositions and methods for modulating Th1, Th17, Th22, or other cells that secrete, or cause other cells to secrete, inflammatory molecules, including, but not limited to, IL-1β, TNF-α, TGF-beta, IFN-γ, IL-17, IL-6, IL-23, IL-22, IL-21, and MMPs.
It is another object of the invention to provide compositions and methods for modulation of at least two immune pathways that result in the secretion of one or more inflammatory molecules, including, but not limited to, IL-1β, TNF-α, TGF-beta, IFN-γ, IL-17, IL-6, IL-23, IL-22, IL-21, and MMPs, preferably by Th1, Th17 or Th22 cells.
It is another object of the invention to provide compositions and methods for modulation of the Treg cells and pathways, such as IL-10 and TGF-beta secretion.
It is another object of the invention to provide compositions and methods for modulating the proinflammatory activity of Th1, Th17 or Th22 T cells while simultaneously increasing or promoting the activity of Tregs.
It is an object of the invention to provide compositions containing B7-H4 polypeptides that function to decrease or inhibit antigen-specific proliferation of T cells, decrease or inhibit production of pro-inflammatory molecules by T cells, decrease or inhibit differentiation and effector function of Th1, Th17 or Th22 cells, and decrease or inhibit survival of Th1, Th17 or Th22 cells.
It is another object of the invention to provide compositions containing B7-H4 polypeptides that function to increase or promote the activity of Tregs, increase the production of inflammatory molecules such as IL-10 from Tregs, increase the differentiation of naïve T cells into Tregs, increase the number of Tregs, or increase the survival of Tregs.
It is another object of the invention to provide compositions containing B7-H4 polypeptides that function to inhibit or decrease the proinflammatory activity of Th1, Th17 or Th22 T cells while simultaneously increasing or promoting the activity of Tregs.
It is another object of the invention to provide isolated nucleic acid molecules encoding B7-H4 compositions.
It is another object of the invention to provide cells containing vectors that express nucleic acid molecules encoding B7-H4 compositions.
It is still a further object of the invention to provide methods for decreasing or inhibiting pro-inflammatory T cell activation by contacting them with B7-H4 compositions.
It is still a further object of the invention to provide methods for the treatment of inflammatory and autoimmune diseases and disorders.
It is still a further object of the invention to provide methods for administering B7-H4 compositions, nucleic acids encoding the same, or cells transfected or transduced with nucleic acids encoding B7-H4 compositions to a mammal in need thereof.
It is another object to provide compositions and methods for increasing Treg biological activity.
It is yet another object to provide compositions and methods for inhibiting or reducing eptitope spreading.
It is another object to provide compositions and methods for inhibiting differentiation of naïve T cells into Th1, Th17, Th22, or other cells that secrete, or cause other cells to secrete, pro-inflammatory molecules, including, but not limited to, IL-1β, TNF-α, TGF-beta, IFN-γ, IL-17, IL-6, IL-23, IL-22, IL-21, and MMPs.
It is another object to provide compositions and methods for inhibiting the differentiation and maturation of immature antigen-presenting cells.
It is another object of the invention to monitor patients who would benefit from treatment with the compositions and methods disclosed by measuring the levels of biomarkers such as inflammatory chemokines, cytokines or other molecules, or gene expression of biomarkers in the patient.
It is another object of the invention to identify patients who would benefit from treatment with the compositions and methods disclosed by measuring the levels of biomarkers such as inflammatory chemokines, cytokines or other molecules in the patient.
It is another object of the invention to identify patients who would benefit from treatment with the compositions and methods disclosed by identifying patients with polymorphisms in genes encoding biomarkers such as inflammatory chemokines, cytokines or other molecules.
It is another object of the invention to provide combination therapies for treating patients with inflammatory and autoimmune diseases and disorders.
It is another object of the invention to provide compositions for treating patients who do not respond to TNF blockers.
It is another object of the invention to provide compositions for treating chronic and persistent inflammation.